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mGlu8 receptor

Family: Metabotropic glutamate receptors

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Agonists
Antagonists
Transduction Mechanisms
Tissue Distribution
Expression Datasets
Functional Assays
Physiological Functions
Physiological Consequences of Altering Gene Expression
Phenotypes, Alleles and Disease Models
Biologically Significant Variants
General Comments
References
Gene and Protein Information
class C G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 908 7q31.3-q32 GRM8 glutamate receptor, metabotropic 8 27,36
Mouse 7 908 6 A3 Grm8 glutamate receptor, metabotropic 8 6
Rat 7 908 4q22 Grm8 glutamate receptor, metabotropic 8 26
Previous and Unofficial Names
mGluR8
GRM8
Gprc1h
GLUR8
mGlu8
mGluR8b
mGlur
G protein-coupled receptor family C group 1 member H
G protein-coupled receptor, family C, group 1, member H
glutamate receptor, metabotropic 8
metabotropic glutamate receptor 8
metabotropic glutamate receptor subtype 8b
Database Links
ChEMBL Target 11281 (Hs), 12951 (Mm), 11058 (Rn)
DrugBank Target 927 (Hs)
Ensembl ENSG00000179603 (Hs), ENSMUSG00000024211 (Mm), ENSRNOG00000021468 (Rn)
Entrez Gene 2918 (Hs), 14823 (Mm), 60590 (Rn)
GeneCards GRM8 (Hs)
GenitoUrinary Development Molecular Anatomy Project Grm8 (Mm)
HomoloGene 654 (Hs)
Human Protein Reference Database 03071 (Hs)
InterPro O00222 (Hs), P47743 (Mm), P70579 (Rn)
KEGG Gene hsa:2918 (Hs), mmu:14823 (Mm), rno:60590 (Rn)
OMIM 601116 (Hs)
PharmGKB Gene PA28997 (Hs)
PhosphoSitePlus O00222 (Hs), P47743 (Mm), P70579 (Rn)
Protein Ontology (PRO) PRO:000008270 (Hs)
RefSeq Nucleotide NM_000845 (Hs), NM_008174 (Mm), NM_022202 (Rn)
RefSeq Protein NP_000836 (Hs), NP_032200 (Mm), NP_071538 (Rn)
TreeFam ENSG00000179603 (Hs), ENSMUSG00000024211 (Mm), ENSRNOG00000021468 (Rn)
UniGene Hs. 449625 (Hs)
UniProt O00222 (Hs), P47743 (Mm), P70579 (Rn)
Wikipedia mGlu8 receptor
Metabotropic glutamate receptors
Search for 3D structures on the PDB
Search by keyword: Metabotropic glutamate receptors mGlu8 receptor Search by accession number: P70579, O00222, P47743
Natural/Endogenous Ligand(s)
L-glutamic acid
Comments: Other endogenous ligands include L-aspartic acid, L-SOP, NAAG and L-cysteine sulphinic acid
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
[3H]AP4 Hs Full agonist 6.6 – 6.7 pKd 19
(S)-3,4-DCPG Hs Full agonist 7.5 pEC50 32
(R,S)-4-PPG Hs Full agonist 6.7 pEC50 9-10,32
L-AP4 Rn Full agonist 6.2 pEC50 26
L-CCG-I Rn Full agonist 6.2 pEC50 26
D-AP4 Hs Full agonist 5.5 pEC50 36
ACPT-I Rn Partial agonist 5.1 pEC50 5
LY354740 Hs Full agonist 5.1 pEC50 19
(1S,3R)-ACPD Hs Full agonist 4.4 pEC50 36
(1S,3R)-ACPD Rn Full agonist 4.3 pEC50 26
L-AP4 Hs Full agonist 7.0 – 7.2 pIC50 19
L-SOP Hs Full agonist 6.2 – 7.2 pIC50 19,36
L-CCG-I Hs Full agonist 6.1 – 6.3 pIC50 19
L-glutamic acid Hs Full agonist 5.0 – 5.7 pIC50 19,36
View species-specific agonist tables
Agonist Comments
(S)-3,4-DCPG is the only selective agonist for mGlu8. Affinity is 100 fold higher than on mGlu4 and mGlu6. L-AP4, L-SOP, (RS)-4-PPG are selective for group III mGlu receptors.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
CPPG Rn Antagonist 6.3 pKi 23
LY341495 Hs Antagonist 6.8 pIC50 13
MAP4 Rn Antagonist 5.1 – 7.6 pIC50 23,26
DCG-IV Hs Antagonist 5.5 pIC50 19
MSOP Rn Antagonist 5.3 pIC50 24
MPPG Hs Antagonist 4.33 pIC50 36
View species-specific antagonist tables
Antagonist Comments
There is no specific mGlu8 antagonist.
CPPG, α-MSOP, MAP4 are group III selective antagonists.

Explore drug-target interactions for this set of compounds using iPHACE

Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
Comments:  In RGT and CHO cells stably transfected with recombinant rat or human mGlu8 receptors.
References:  6,26,36
Tissue Distribution
Olfactory bulb, piriform cortex, pontine nuclei > neocortex, reticular thalamic nucleus, basolateral amygdaloid nuclear group.
Species:  Human
Technique:  in situ hybridisation.
References:  4
Olfactory bulb (granule cells, mitral cells), olfactory tubercule, mammillary body, retina.
Species:  Mouse
Technique:  in situ hybridisation.
References:  6
Superficial layer of the olfactory tubercle, piriform cortex, periamygdaloid cortical region.
Species:  Rat
Technique:  Immunohistochemistry.
References:  35
Retina.
Species:  Rat
Technique:  immunocytochemistry.
References:  15
Pancreatic islets (alpha cells).
Species:  Rat
Technique:  RT-PCR.
References:  34
Enteric nervous system.
Species:  Rat
Technique:  RT-PCR, Western blotting and immunocytochemistry.
References:  33
Basal ganglia: reticular thalamic nucleus > premotor cortex > nucleus accumbens > anteroventral thalamus, parafasicular nucleus, substantia nigra pars compacta, striatum, subthalamic nucelus > entopeduncular nucleus, globus pallidus, substantia nigra pars reticular, ventrolateral thalamus, ventromedial thalamus.
Species:  Rat
Technique:  in situ hybridisation.
References:  20
Pancreatic islets.
Species:  Rat
Technique:  RT-PCR and Western blotting.
References:  1
Olfactory bulb (granule cells, mitral cells), piriform cortex (pyramidal cells), pontine gray, lateral reticular nucleus of the thalamus and other nuclei of basal ganglia > cerebral cortex, hippocampus, cerebellum, mammillary body.
Species:  Rat
Technique:  in situ hybridisation.
References:  26
Presynaptic active zone of both excitatory and GABAergic axon terminals.
Species:  Rat
Technique:  Western blotting.
References:  8
Presynaptic active zone of GABAergic axon terminals.
Species:  Rat
Technique:  immunocytochemistry.
References:  14
Nodose ganglia and nucleus solitary tract.
Species:  Rat
Technique:  RT-PCR
References:  12
Hippocampus: presynaptic terminals of the lateral perforant path in the dendate gyrus and CA3 regions.
Species:  Rat
Technique:  Immunohistochemistry.
References:  30
Expression Datasets

Click here to show/hide data

Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Measurement of GIRK-mediated K+ currents in Xenopus oocytes transfected with the mGlu8 receptor.
Species:  Rat
Tissue:  Xenopus oocytes.
Response measured:  Stimulation of K+ currents.
References:  26
Measurement of cAMP levels in RGT cells transfected with the mGlu8 receptor.
Species:  Human
Tissue:  RGT cells.
Response measured:  Inhibition of cAMP accumulation.
References:  36
Measurement of IP levels in HEK 293 cells transfected with the mGlu8 receptor and Gqi9.
Species:  Rat
Tissue:  HEK 293 cells.
Response measured:  IP formation.
References:  5
Measurement of N-type Ca2+ currents in superior cervical neurons transfected with the mGlu8 receptor.
Species:  Rat
Tissue:  Superior cervical neurons.
Response measured:  Inhibition of N-type Ca2+ currents.
References:  11
Physiological Functions
Inhibition of synaptic transmission at lateral perforant path input to dendate gyrus.
Species:  Mouse
Tissue:  Brain
References:  3,37
Modulation of the fast component of the dorsal root-evoked ventral root potential.
Species:  Rat
Tissue:  Spinal Cord
References:  32
Inhibition of sound-induced seizures in DBA/2 mice
Species:  Mouse
Tissue:  Brain
References:  21
Modulation of synaptic transmission in the retino-collicular pathway.
Species:  Rat
Tissue:  Brain
References:  25
mGlu8 stimulation induces c-Fos in stress-related brain regions.
Species:  Mouse
Tissue:  Brain
References:  17
Regulation of transmitter release in the supraoptic nucleus of the rat hypothalamus.
Species:  Rat
Tissue:  Brain
References:  22
Attenuation of alcohol self-administration.
Species:  Rat
Tissue:  In vivo.
References:  2
Acquisition and expression of conditioned fear are inhibited by mGlu8 stimulation in the amygdala.
Species:  Rat
Tissue:  In vivo.
References:  28
Physiological Consequences of Altering Gene Expression
Increased anxiety-related behavior in mGlu8-null mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  7,18
Absence of inhibition of synaptic transmission at the perforant path by L-AP4 in mGlu8-null mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  3,37
Absence of inhibition of synaptic transmission at the perforant path by DCPG in mGlu8-null mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  37
mGlu8 knockout mice exhibit an increased c-Fos expression in the thalamus following the elevated plus maze test.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  16
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Grm8tm1Duv Grm8tm1Duv/Grm8tm1Duv
B6.129S1-Grm8		 MGI:1351345  MP:0001417 decreased exploration in new environment PMID: 16045496 
Grm8tm1En Grm8tm1En/Grm8tm1En
involves: 129S1/Sv * 129X1/SvJ * C57BL/6		 MGI:1351345  MP:0008874 decreased physiological sensitivity to xenobiotic PMID: 12213276 
Grm8tm1Duv Grm8tm1Duv/Grm8tm1Duv
B6.129S1-Grm8		 MGI:1351345  MP:0001522 impaired swimming PMID: 16045496 
Grm8tm1Duv Grm8tm1Duv/Grm8tm1Duv
B6.129S1-Grm8		 MGI:1351345  MP:0001363 increased anxiety-related response PMID: 16045496 
Grm8tm1Duv Grm8tm1Duv/Grm8tm1Duv
B6.129S1-Grm8		 MGI:1351345  MP:0001260 increased body weight PMID: 16045496 
Grm8tm1Duv Grm8tm1Duv/Grm8tm1Duv
B6.129S1-Grm8		 MGI:1351345  MP:0005458 increased percent body fat PMID: 16045496 
Grm8tm1Duv Grm8tm1Duv/Grm8tm1Duv
B6.129S1-Grm8		 MGI:1351345  MP:0005331 insulin resistance PMID: 16045496 
Biologically Significant Variants
Alternative splicing results in a different C-terminus.
Type:  Splice variants.
Species:  Rat
References:  4
Alternative splicing results in a different C-terminus.
Type:  Splice variants.
Species:  Human
References:  19
A second splice variant introduces a stop codon before the 7 transmembrane domain resulting in a potentially secreted isoform of the receptor.
Type:  Splice variants.
Species:  Human
References:  19
mGlu8 can be sumoylated.
Type: 
Species:  Rat
References:  31
General Comments
Schoepp et al., (1999) [29] and Pin & Acher (2002) [24] review and compare the pharmacology of mGlu receptors.

REFERENCES

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1. Brice, N. L., Varadi, A., Ashcroft, S. J. and Molnar, E. (2002) Metabotropic glutamate and GABA(B) receptors contribute to the modulation of glucose-stimulated insulin secretion in pancreatic beta cells. Diabetologia., 45: 242-252. [PMID:11935156]

2. Bäckström, P. and Hyytiä, P. (2005) Suppression of alcohol self-administration and cue-induced reinstatement of alcohol seeking by the mGlu2/3 receptor agonist LY379268 and the mGlu8 receptor agonist (S)-3,4-DCPG. Eur J Pharmacol, 528: 110-118. [PMID:16324694]

3. Cai, Z., Saugstad, J. A., Sorensen, S. D., Ciombor, K. J., Zhang, C., Schaffhauser, H., Hubalek, F., Pohl, J., Duvoisin, R. M. and Conn, P. J. (2001) Cyclic AMP-dependent protein kinase phosphorylates group III metabotropic glutamate receptors and inhibits their function as presynaptic receptors. J Neurochem., 78: 756-766. [PMID:11520896]

4. Corti, C., Restituito, S., Rimland, J. M., Brabet, I., Corsi, M., Pin, J-P. and Ferragutti, F. (1998) Cloning and characterization of alternative mRNA forms for the rat metabotropic glutamate receptors mGluR7 and mGluR8. Eur. J. Neurosci., 10: 3629-3641. [PMID:9875342]

5. de Colle, C., Bessis, A. S., Bockaert, J., Acher, F. and Pin, J. P. (2000) Pharmacological characterization of the rat metabotropic glutamate receptor type 8a revealed strong similarities and slight differences with the type 4a receptor. Eur J Pharmacol, 394: 17-26. [PMID:10771029]

6. Duvoisin, R. M., Zhang, C. and Ramonell, K. (1995) A novel metabotropic glutamate receptor expressed in the retina and olfactory bulb. J. Neurosci., 15: 3075-3083. [PMID:7722646]

7. Duvoisin, R. M., Zhang, C., Pfankuch, T. F., O'Connor, H., Gayet-Primo, J., Quraishi, S. and Raber, J. (2005) Increased measures of anxiety and weight gain in mice lacking the group III metabotropic glutamate receptor mGluR8. Eur J Neurosci, 22: 425-436. [PMID:16045496]

8. Ferraguti, F., Klausberger, T., Cobden, P., Baude, A., Roberts, J. D., Szucs, P., Kinoshita, A., Shigemoto, R., Somogyi, P. and Dalezios, Y. (2005) Metabotropic glutamate receptor 8-expressing nerve terminals target subsets of GABAergic neurons in the hippocampus. J Neurosci, 25: 10520-10536. [PMID:16280590]

9. Gasparini, F., Bruno, V., Battaglia, G., Lukic, S., Leonhardt, T., Inderbitzin, W., Laurie, D., Sommer, B., Varney, M. A., Hess, S. D., Johnson, E. C., Kuhn, R., Urwyler, S., Sauer, D., Portet, C., Schmutz, M., Nicoletti, F. and Flor, P. J. (1999) (R,S)-4-phosphonophenylglycine, a potent and selective group III metabotropic glutamate receptor agonist is anticonvulsive and neuroprotectivein vivo. J. Pharmacol. Exp. Ther., 289: 1678-1687. [PMID:10336568]

10. Gasparini, F., Inderbitzin, W., Francotte, E., Lecis, G., Richert, P., Dragic, Z., Kuhn, R. and Flor, P. J. (2000) (+)-4-phosphonophenylglycine (PPG) a new group III selective metabotropic glutamate receptor agonist. Bioorg Med Chem Lett, 10: 1241-1244. [PMID:10866390]

11. Guo, J. and Ikeda, S. R. (2005) Coupling of metabotropic glutamate receptor 8 to N-type Ca2+ channels in rat sympathetic neurons. Mol Pharmacol, 67: 1840-1851. [PMID:15755905]

12. Hoang, C. J. and Hay, M. (2001) Expression of metabotropic glutamate receptors in nodose ganglia and the nucleus of the solitary tract. Am J Physiol Heart Circ Physiol., 281: H457-H462. [PMID:11406515]

13. Kingston, A. E., Ornstein, P. L., Wright, R. A., Johnson, B. G., Mayne, N. G., Burnett, J. P., Belagaje, R., Wu, S. and Schoepp, D. D. (1998) LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors. Neuropharmacology., 37: 1-12. [PMID:9680254]

14. Kogo, N., Dalezios, Y., Capogna, M., Ferraguti, F., Shigemoto, R. and Somogyi, P. (2004) Depression of GABAergic input to identified hippocampal neurons by group III metabotropic glutamate receptors in the rat. Eur J Neurosci, 19: 2727-2740. [PMID:15147307]

15. Koulen, P., Kuhn, R., Wassle, H. and Brandstatter, J. H. (1999) Modulation of the intracellular calcium concentration in photoreceptor terminals by a presynaptic metabotropic glutamate receptor. Proc Natl Acad Sci U S A., 96: 9909-9914. [PMID:10449793]

16. Linden, A. M., Baez, M., Bergeron, M. and Schoepp, D. D. (2003) Increased c-Fos expression in the centromedial nucleus of the thalamus in metabotropic glutamate 8 receptor knockout mice following the elevated plus maze test. Neuroscience., 121: 167-178. [PMID:12946709]

17. Linden, A. M., Bergeron, M., Baez, M. and Schoepp, D. D. (2003) Systemic administration of the potent mGlu8 receptor agonist (S)-3,4-DCPG induces c-Fos in stress-related brain regions in wild-type, but not mGlu8 receptor knockout mice. Neuropharmacology., 45: 473-483. [PMID:12907308]

18. Linden, A. M., Johnson, B. G., Peters, S. C., Shannon, H. E., Tian, M., Wang, Y., Yu, J. L., Koster, A., Baez, M. and Schoepp, D. D. (2002) Increased anxiety-related behavior in mice deficient for metabotropic glutamate 8 (mGlu8) receptor. Neuropharmacology., 43: 251-259. [PMID:12213279]

19. Malherbe, P., Kratzeisen, C., Lundstrom, K., Richards, J. G., Faull, R. L. M. and Mutel, V. (1999) Cloning and functional expression of alternative spliced variants of the human metabotropic glutamate receptor 8. Brain Res. Mol. Brain Res., 67: 201-210. [PMID:10216218]

20. Messenger, M. J., Dawson, L. G. and Duty, S. (2002) Changes in metabotropic glutamate receptor 1-8 gene expression in the rodent basal ganglia motor loop following lesion of the nigrostriatal tract. Neuropharmacology., 43: 261-271. [PMID:12213280]

21. Moldrich, R. X., Beart, P. M., Jane, D. E., Chapman, A. G. and Meldrum, B. S. (2001) Anticonvulsant activity of 3,4-dicarboxyphenylglycines in DBA/2 mice. Neuropharmacology., 40: 732-735. [PMID:11311902]

22. Panatier, A., Poulain, D. A. and Oliet, S. H. (2004) Regulation of transmitter release by high-affinity group III mGluRs in the supraoptic nucleus of the rat hypothalamus. Neuropharmacology., 47: 333-341. [PMID:15275822]

23. Peltekova, V., Han, G., Soleymanlou, N. and Hampson, D. R. (2000) Constraints on proper folding of the amino terminal domains of group III metabotropic glutamate receptors. Brain Res Mol Brain Res, 76: 180-190. [PMID:10719229]

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25. Pothecary, C. A., Jane, D. E. and Salt, T. E. (2002) Reduction of excitatory transmission in the retino-collicular pathway via selective activation of mGlu8 receptors by DCPG. Neuropharmacology., 43: 231-234. [PMID:12213277]

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27. Scherer, S. W., Soder, S., Duvoisin, R. M. and Huizenga, J. J. (1997) The human metabotropic glutamate receptor 8 (GRM8) gene: A disproportionately large gene located at 7q31.3-q32.1. Genomics, 44: 232-236. [PMID:9299241]

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30. Shigemoto, R., Kinoshita, A., Wada, E., Nomura, S., Ohishi, H., Takada, M., Flor, P. J., Neki, A., Abe, T., Nakanishi, S. and Mizuno, N. (1997) Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus. J Neurosci., 17: 7503-7522. [PMID:9295396]

31. Tang, Z., El Far, O., Betz, H. and Scheschonka, A. (2005) Pias1 interaction and sumoylation of metabotropic glutamate receptor 8. J Biol Chem, 280: 38153-38159. [PMID:16144832]

32. Thomas, N. K., Wright, R. A., Howson, P. A., Kingston, A. E., Schoepp, D. D. and Jane, D. E. (2001) (S)-3,4-DCPG, a potent and selective mGlu8a receptor agonist, activates metabotropic glutamate receptors on primary afferent terminals in the neonatal rat spinal cord. Neuropharmacology., 40: 311-318. [PMID:11166323]

33. Tong, Q. and Kirchgessner, A. L. (2003) Localization and function of metabotropic glutamate receptor 8 in the enteric nervous system. Am J Physiol Gastrointest Liver Physiol., 285: G992-G1003. [PMID:12829438]

34. Tong, Q., Ouedraogo, R. and Kirchgessner, A. L. (2002) Localization and function of group III metabotropic glutamate receptors in rat pancreatic islets. Am J Physiol Endocrinol Metab., 282: E1324-E1333. [PMID:12006363]

35. Wada, E., Shigemoto, R., Kinoshita, A., Ohishi, H. and Mizuno, N. (1998) Metabotropic glutamate receptor subtypes in axon terminals of projection fibers from the main and accessory olfactory bulbs: a light and electron microscopic immunohistochemical study in the rat. J Comp Neurol., 393: 493-504. [PMID:9550154]

36. Wu, S., Wright, R. A., Rockey, P. K., Burgett, S. G., Arnold, P. R., Johnson, B. G., Schoepp, D. D. and Belagaje, R. (1998) Group III human metabotropic glutamate receptors 4, 7, and 8: molecular cloning, functional expression, and comparison of pharmacological properties in RGT cells. Brain Res. Mol. Brain Res., 53: 88-97. [PMID:9473604]

37. Zhai, J., Tian, M. T., Wang, Y., Yu, J. L., Koster, A., Baez, M. and Nisenbaum, E. S. (2002) Modulation of lateral perforant path excitatory responses by metabotropic glutamate 8 (mGlu8) receptors. Neuropharmacology., 43: 223-230. [PMID:12213276]

To cite this database page, please use the following:

Francine Acher, P. Jeffrey Conn, Robert Duvoisin, Francesco Ferraguti, Peter J. Flor, David Hampson, Michael P. Johnson, James Monn, Shigetada Nakanishi, Ferdinando Nicoletti, Jean-Philippe Pin, Darryle D. Schoepp, Ryuichi Shigemoto.
Metabotropic glutamate receptors: mGlu8 receptor. Last modified on 31/01/2013. Accessed on 19/06/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=296.


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